ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2281A>G (p.Arg761Gly) (rs199876321)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129031 SCV000172939 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-23 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000195792 SCV000254294 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 761 of the MSH6 protein (p.Arg761Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs199876321, ExAC 0.03%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 140836). An algorithm developed specifically for the MSH6 gene suggests that this variant is likely to be deleterious (PMID: 23621914). General algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). These predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000657020 SCV000279316 uncertain significance not provided 2018-10-15 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2281A>G at the cDNA level, p.Arg761Gly (R761G) at the protein level, and results in the change of an Arginine to a Glycine (AGG>GGG). This variant was observed in several individuals that underwent testing for hereditary colon cancer, one of which was also identified to have a single MUTYH pathogenic variant (Rey 2017, Ricker 2017, Martin-Morales 2018). MSH6 Arg761Gly was also identified in an individual with a personal history of melanoma (Yehia 2018). MSH6 Arg761Gly was observed at an allele frequency of 0.035% (12/33,574) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is located in the Lever domain (Warren 2007, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Arg761Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657020 SCV000601528 uncertain significance not provided 2019-05-17 criteria provided, single submitter clinical testing
Color RCV000129031 SCV000685275 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-19 criteria provided, single submitter clinical testing
Counsyl RCV000662484 SCV000784983 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-03-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002443 SCV001160383 uncertain significance not specified 2019-03-26 criteria provided, single submitter clinical testing The MSH6 c.2281A>G; p.Arg761Gly variant (rs199876321) is reported in two probands who underwent hereditary colorectal cancer testing (Rey 2017). This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 140836). It is found in the general population with an overall allele frequency of 0.006% (15/251138 alleles) Genome Aggregation Database. The arginine at codon 761 is moderately conserved, but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Rey JM et al. Improving Mutation Screening in Patients with Colorectal Cancer Predisposition Using Next-Generation Sequencing. J Mol Diagn. 2017 Jul;19(4):589-601.
Illumina Clinical Services Laboratory,Illumina RCV000662484 SCV001300702 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Integrated Genetics/Laboratory Corporation of America RCV001002443 SCV001338334 uncertain significance not specified 2020-02-25 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2281A>G (p.Arg761Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251138 control chromosomes (gnomAD). c.2281A>G has been reported in the literature in individuals affected with Hereditary Non-Polyposis Colon Cancer and melanoma (e.g. Martin-Morales_2018, Rey_2017, Ricker_2017, Yehia_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Non-Polyposis Colon Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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